Benzothiazolesulfonamides and method of preparing the same



Patented May 6, 1952 BEN ZOTHIAZOLESULFONAMIDES AND METHOD OF PREPARINGTHE SAME James W. Clapp, Darien, and Richard 0. Roblin, Jr., Riverside,Conn., assignors to American Cyanamid Company, New York, N. Y., acorporation of Maine No Drawing. Application April 8, 1950,

Serial No. 154,884

This invention relates to substituted benzothiazolesulfonamides and tomethods of preparin'g's'aid compounds.

It is generally recognized that numerous functions and actions of thehuman body are largely controlled by a wide variety of enzymes. One ofthese numerous enzymes is called carbonic anhydrase because it isinvolved in the metabolism of carbon dioxide. This enzyme has otherfunctions too, since it can catalyze the conversion of carbon dioxide tocarbonic acid. The excretion of acid by the kidneys is thought to be dueto this function of carbonic anhydrase.

The excretion of acid by the kidneys is one method by which the bodynormally conserves salt. The maintenance of a constant ratio of salt towater in the body is of utmost importance for general health. In somecases, however,-excess salt and water accumulate in the tissues causinga condition which is called edema. It is frequently encountered inassociation withfcon gestiveheart failure. The excess salt and watercause an uncomfortable swelling of the tissues and place an added strainon the heart. To combat this condition so-called diuretic agents aresometimes used to promote the excretion of the 12 Claims. (Cl. 260306.6)

2 stituents such as halogen, alkyl, alkoxy, hydroxyl and the like.

The compounds of the present invention are, in general, whitecrystalline solids, soluble inmost organic solvents and having definitemelting points.

The compounds are prepared by dissolving a mercapto-benzothiazole in anaqueous acid solution and passing in chlorine gas to produce thecorresponding sulfonyl chloride. This product is then treated with anexcess of ammonia in the excess salt and water. These agents, for themost administered in adequate doses.

We have now found that substituted benzo- 'thiazolesulfonamides showmuch greater activity than sulfanilamide in inhibiting carbonicanhydrase. These compounds are new and may be illustrated by thefollowing general formula:

'/CS 02N\ N in which R and R are hydrogen, alkyl or heterocyclicradicals. The benzene portion of the benzothiazole nucleus may also havepresent sub- ,requires a large excess of chlorine.

form of liquid ammonia or ammonium hydroxide to produce theunsubstituted sulfonamides and with an alkylamine or a heterocyclicamine to produce compounds substituted on the. sulfonamide group. 7 j

The reaction time is not particularly critical but chlorine should. beadded at such a rate that the temperature does not rise excessively anduntil an excess is present in the reaction mixture. The temperatureduringjthe chlorination is preferably maintained within the range of -l0C. to 25 C. However, during the reaction of the sulfonyl chloride withammonia or an amine, the

= temperature may be increased to about C., de-

pending upon the volatility of the particular amine. Obviously thereaction should be carried out at a temperature below the boilingpointof the amine. Q 4

The compounds of the present invention are active against certainmicro-organisms and are also highly efiective as inhibitors of carbonicanhydrase and for this reason, may be effective in the relief of edemaassociated with. congestive heart failure or in other conditions whereinhibition of carbonic anhydrase is useful.

The following examples illustrate the preparation of representativebenzothiazolesulfonamides from the corresponding mercaptobenzothiazole.All parts are by weight unless otherwise indicated.

EXAMPLE 1 V 2benzothiazolesulfonamide parts of Z-mercaptobenzothiazole(powdered) are suspended in a mixture of 550 parts of glacial aceticacid and 1100 parts of water. This mixture is stirred rapidly in acooling bath while chlorine is introduced in multiple fine "streams at arapid rate for about three hours. The temperature of the mixture isheldbelow 8-,C. to minimize decomposition. The-chlorine treatmentisfcontinued until a test of the suspended solid shows it to be mostlysoluble in ethylene chloride; this The crude product is unstable atordinary temperatures, but

is more stable after purification. The crude 2- benzothiazolesulfonylchloride is then filtered and washed thoroughly with ice-cold water. Itcan be recrystallized from a large volume of ether or petroleum etherand when pure it forms white crystals, melting point 108-110 C.

30 parts of damp 2-benzothiazolesulfonyl chloride is added to 60 partsof concentrated ammonium hydroxide (d=0.90) with good stirring. Thetemperature of the mixture is not critical up to at least 40 C. Themixture is stirred for one to two hours, then filtered. The filtrate istreated with activated charcoal, then refiltered, and the productprecipitated by neutralization, filtered, washed with water and dried.It is purified by recrystallization from ethylene chloride or from alarge volume of water or by repeated solution in dilute alkali andreprecipitation with acid. Impurities are removed from solution withactivated charcoal. The pure product is a white crystalline solid,melting point 1'77.5 0., with bubbling. The yield based on2-mercaptobenzothiazo1e was about 36%.

The yields are improved somewhat by the use of excess anhydrous liquidammonia for reaction with the sulfonyl chloride. The excess ammonia isthen allowed to evaporate and the crude sulfonamide is purified asindicated above. Yields up to 58% (crude) are obtained by this method.

EXAMPLE 2 2-benzothiazolesulfon-n-propylamide Six parts of purifiedZ-benzothiazolesulfonyl chloride are added gradually to 50 parts of dryn-propylamine, with stirring and chilling. The mixture is stirred for anadditional period and the excess amine then evaporated. The residue istriturated with water to produce crystallization. The solid is filteredand washed with water, then redissolved in an excess of dilute sodiumhydroxide. The solution is treated with activated charcoal, filtered,and neutralized with acid. The precipitate is filtered, washed withwater, and dried, then recrystallized from a large volume of carbontetrachloride. Yield, 96% of theoretical. The pure product is a white,crystalline solid, melting point 101-101.5 C. It is soluble in ethylacetate, ethylene chloride, benzene, hot carbon tetrachloride and hothexane.

EXAMPLE 3 2wbenzothiaeolesulfiovi-di-n-butyiamicie EXAMPLE 4 N-(2thiazolyZ) benzothiazole- Z-sulfonamide 7.4parts of purifiedZ-benzothiazole sulfonyl chloride are added gradually to a mixture of 20parts of 2-aminothiazole and 50 parts of dry pryidine with stirring andchilling. Solution is soon complete. Stirring is continued for abouthour without chilling, and the mixture allowed to stand for two days.Water is added, precipitating a gum. The mixture is acidified, and thegum then washed well with water. It is then extracted with dilutealkali, and filtered. The filtrate is neutralized with acid; the productslowly crystallizes. It is filtered. and again extracted with dilutealkali and filtered. Acidification of the filtrate again gives slowcrystallization. The product is filtered, dried, and recrystallized fromethylene chlorigle three times. The pure compound is a while crystallinesolid, melting point 148-153 C. (not sharp), with charring and bubbling.As thus produced it is a hemihydrate.

We claim:

1. Compounds of the group consisting of those having the generalformula:

in which R and R. are members of the group consisting of hydrogen, loweralkyl and Z-thiazolyl radicals.

2. Compounds of the group consisting of those having the generalformula:

s p o-s omen in which R is a lower alkyl radical.

3. 2-benzothiazolesulfonamide. 4. 2-benzothiazolesulfon-n-propylamide.5. Z-benzothiazolesulfon-di-n-butylamide. 6. N- (2-thiazolyl)benzothiazole-2-sulfonamide. 7. A method of preparing compounds havingthe general formula:

/CSO2N N/ .RI

in which R and R are members of the group consisting of hydrogen, loweralkyl and 2-thiazolyl radicals which comprises reacting amercaptobenzothiazole with chlorine in the presence of an aqueous acidsolution and subsequently with a member of the group consisting ofammonia, a lower alkyl amine and Z-aminothiazole. 8. A method ofpreparing compounds having the general formula:

mixing the resulting product with N-propylamine and recovering saidcompound therefrom.

11. A method of preparing Z-benzothiazolesulfon-di-n-butylamide whichcomprises dissolving 2-mercaptobenzothiazole in aqueous acetic acidsolution, passing chlorine into said solution, mixing the resultingproduct with di-n-butylamine and recovering the said product therefrom.

12. A method of preparing N-(Z-thiazolyD- benzothiazole v2 sulfonamidewhich comprises dissolving Z-mercaptobenzothiazole in aqueous acidsolution, passing chlorine into said solution,

mixing the resulting product with Z-aminothiazole and recovering saidproduct therefrom.

,JAMES W. CLAPP.

RICHARD O. ROBLIN, JR.

REFEREFHJES CITED file of this patent:

Number UNITED STATES PATENTS Name Date Roblin Jan. 9, 1945

1. COMPOUNDS OF THE GROUP CONSISTING OF THOSE HAVING THE GENERALFORMULA: